The increasing incidence of obesity is a major health issue facing the USA. Moreover, the mechanisms underlying anorexia nervosa remain poorly understood. Fortunately, in the past decade several key hormones and CMS pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like leptin exert its effects which may lead to effective strategies to combat the incidence of obesity and eating disorders. In the past grant period, we sought to delineate the neural substrates through which melanocortin 4 receptors (MC4-Rs) selectively regulate food intake, body weight and glucose homeostasis. We focused on the potential interactions of leptin-regulated neuronal systems and MC4-R systems. Collectively, our data suggests that different sites in the brain mediate different effects of MC4-R agonists to regulate body weight, food intake, and glucose homeostasis. Specifically, we found that neurons in the paraventricular nucleus of the hypothalamus regulate food intake, but do not regulate energy expenditure. In the current proposal, we will extend these observations using our mouse model in which we can selectively reactivate MC4-R expression. We will identify if neurons in the raphe pallidus are sufficient to regulate energy expenditure. We will also determine if reactivation of MC4-Rs in autonomic preganglionic neurons is sufficient to rescue the reduced energy expenditure and diabetes characteristic of MC4-R deficiency. Finally, we will determine is MC4-R expression by autonomic preganglionic neurons is required for normal body weight and glucose homeostasis by selectively deleting MC4-Rs in autonomic preganglionic neurons in mice that express MC4-Rs everywhere else in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK053301-13
Application #
7749574
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (02))
Program Officer
Hyde, James F
Project Start
1998-03-25
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
13
Fiscal Year
2010
Total Cost
$312,259
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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